title: ABSOLUTE CONFIGURATION AND BIOLOGICAL PROPERTIES OF ENANTIOMERS OF CFTR INHIBITOR BPO-27.
abstract: We previously reported benzopyrimido-pyrrolo-oxazinedione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27, (1), which contains a single chiral center, and determined their absolute configuration, activity and metabolic stability. Following separation by chiral supercritical fluid chromatography, theRenantiomer, as determined by x-ray crystallography, inhibited CFTR chloride conductance with IC50~ 4 nM, whileSenantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5 % metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1decayed with t1/2~ 1.6 h and gave sustained therapeutic concentrations in kidney.
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA, 94143-0521 ; Department of Chemistry, University of California, Davis, CA, 95616.
authors.forename: David S
authors.initials: DS
authors.lastname: Snyder
authors.forename: Lukmanee
authors.initials: L
authors.lastname: Tradtrantip
authors.forename: Sailaja
authors.initials: S
authors.lastname: Battula
authors.forename: Chenjuan
authors.initials: C
authors.lastname: Yao
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.forename: James C
authors.initials: JC
authors.lastname: Fettinger
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
keywords: crystallography; cystic fibrosis; polycystic kidney disease; secretory diarrhea